The circadian clock component BMAL1 regulates SARS-CoV-2 entry and replication in lung epithelial cells

Xiaodong Zhuang (1) , Senko Tsukuda (1) , Florian Wrensch (2) , Peter Wing (1) , Mirjam Schilling (1) , James Harris (1) , Helene Borrmann (1) , Sophie Morgan (1) , Jennifer Cane (1) , Laurent Mailly (2) , Nazia Thakur (3) , Carina Conceicao (3) , Harshmeena Sanghani (1) , Laura Heydmann (2) , Charlotte Bach (2) , Anna Ashton (1) , Steven Walsh (1) , Tiong Tan (4) , Lisa Schimanski (1, 4) , Kuan-Ying Huang (5) , Catherine Schuster (2) , Koichi Watashi (6, 7) , Timothy Hinks (1) , Aarti Jagannath (1) , Sridhar Vausdevan (1) , Dalan Bailey (3) , Thomas F. Baumert (2, 8, 9) , Jane Mckeating (1)

1 University of Oxford
2 IVH - Institut de Recherche sur les Maladies Virales et Hépatiques
3 The Pirbright Institute
4 John Radcliffe Hospital [Oxford University Hospital]
5 Chang Gung Memorial Hospital [Taoyuan, Taiwan]
6 National Institute of Infectious Diseases [Tokyo]
7 Tokyo University of Science [Tokyo]
8 IHU Strasbourg - L'Institut hospitalo-universitaire de Strasbourg
9 HUS - Les Hôpitaux Universitaires de Strasbourg

The coronavirus disease 2019 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) coronavirus, is a global health issue with unprecedented challenges for public health. SARS-CoV-2 primarily infects cells of the respiratory tract via spike glycoprotein binding to angiotensin-converting enzyme (ACE2). Circadian rhythms coordinate an organism's response to its environment and can regulate host susceptibility to virus infection. We demonstrate that silencing the circadian regulator Bmal1 or treating lung epithelial cells with the REV-ERB agonist SR9009 reduces ACE2 expression and inhibits SARS-CoV-2 entry and replication. Importantly, treating infected cells with SR9009 limits SARS-CoV-2 replication and secretion of infectious particles, showing that post-entry steps in the viral life cycle are influenced by the circadian system. Transcriptome analysis revealed that Bmal1 silencing induced interferon-stimulated gene transcripts in Calu-3 lung epithelial cells, providing a mechanism for the circadian pathway to limit SARS-CoV-2 infection. Our study highlights alternative approaches to understand and improve therapeutic targeting of SARS-CoV-2.

Mots clés: Microbiology; Molecular biology; Transcriptomics; Virology

Domaines: Médecine humaine et pathologie

Xiaodong Zhuang, Senko Tsukuda, Florian Wrensch, Peter Wing, Mirjam Schilling, et al.. The circadian clock component BMAL1 regulates SARS-CoV-2 entry and replication in lung epithelial cells. iScience, 2021, 24 (10), ⟨10.1016/j.isci.2021.103144⟩. ⟨hal-03603571⟩